Li Qin, Zhang Bing-Hua, Chen Qi, Fu Yaoyao, Zuo Xiang, Lu Peng, Zhang Weiwei, Wang Bingqing
Department of Stomatology, Eye&ENT Hospital, Fudan University, Shanghai, 200031, China.
Shanghai Xuhui District Dental Center, Shanghai, 200032, China.
J Hum Genet. 2025 Apr;70(4):189-194. doi: 10.1038/s10038-025-01317-1. Epub 2025 Jan 28.
Hemifacial microsomia (HFM) is a rare congenital disorder that affects facial symmetry, ear development, and other congenital anomalies. However, known causal genes account for only approximately 6% of patients, indicating the need to discover more pathogenic genes. Association tests demonstrated an association between common variants in SHROOM3 and HFM (P = 1.02E-4 for the lead SNP), while gene burden analysis revealed a significant enrichment of rare variants in HFM patients compared to healthy controls (P = 2.78E-5). We then evaluated the expression patterns of SHROOM3 and the consequences of its deleterious variants. Our study identified 7 deleterious variants in SHROOM3 among the 320 Chinese HFM patients and 2 deleterious variants in two HFM trios, respectively, suggesting a model of dominant inheritance with incomplete penetrance. These variants were predicted to significantly impact SHROOM3 function. Furthermore, the gene expression pattern of SHROOM3 in the pharyngeal arches and the presence of facial abnormalities in gene-edited mice suggest that SHROOM3 plays important roles in facial development. Our findings suggest that SHROOM3 is a likely pathogenic gene for HFM.
半侧颜面短小畸形（HFM）是一种罕见的先天性疾病，会影响面部对称性、耳部发育以及其他先天性异常。然而，已知的致病基因仅占患者的约6%，这表明需要发现更多的致病基因。关联测试表明，SHROOM3基因的常见变异与HFM之间存在关联（领先单核苷酸多态性的P值为1.02E-4），而基因负担分析显示，与健康对照相比，HFM患者中罕见变异显著富集（P值为2.78E-5）。然后，我们评估了SHROOM3的表达模式及其有害变异的后果。我们的研究在320例中国HFM患者中分别鉴定出SHROOM3基因的7种有害变异，在两个HFM三联体中鉴定出2种有害变异，提示为一种具有不完全外显率的显性遗传模式。这些变异预计会显著影响SHROOM3的功能。此外，SHROOM3在咽弓中的基因表达模式以及基因编辑小鼠中面部异常的存在表明，SHROOM3在面部发育中起重要作用。我们的研究结果表明，SHROOM3可能是HFM的致病基因。
